This Specialized Center for Cell Therapeutics proposal aims to develop cellular cardiomyoplasty for the treatment of ischemic heart disease, both post-myocardial infarction left ventricular dysfunction as well as chronic ischemic cardiomyopathy. Currently, there is extraordinary enthusiasm for the development of cell-based therapies for diseases resulting from ischemic damage to the myocardium. Rapid advances have been made in animal models and preliminary clinical trials suggest that cardiac function in acute and chronic heart disease may be improved. Currently the bone marrow remains as a highly promising source of precursor cells for cardiac repair. Our group has been involved in collaboration with Osiris Therapeutics in developing bone-marrow derived mesenchymal stem cells (MSCs) for the use of cellular cardiomyoplasty, and the results of this work have led to the upcoming initiation of the first clinical trial of this cell type for humans with myocardial infarction. In addition, cardiac stem cells have now been identified that can be amplified in culture as a source of cells for cardiac repair. This proposal is based upon extensive basic and preclinical data supporting the value of both MSCs and cardiac stem cells (CSCs) for cellular cardiomyoplasty. A major strength of the approach is our ability to prepare adequate numbers of cardiac stem cells from biopsy specimens for use in therapeutic applications. The approach is three-fold with substantial synergies. First, in Project 1 MSCs will be explored in clinical trials of humans with ischemic cardiomyopathy based on an existing extensive pre-clinical database, an established safety record in humans, and already-planned clinical trials for patients with acute myocardial infarction. Second, we will concurrently in Project 2 continue characterizing CSCs obtained from humans and perform relevant preclinical experiments. Finally, based on the substantial experience obtained in Project 1 with delivery techniques and efficacy monitoring developed, and the cellular methods perfected in Project 2, we will perform clinical trials of CSCs in Project 3. Together, this program will have the capability of performing highly-relevant and clinically informative trials that will be guided and refined by the latest advances in basic cell biology.